Semantic, factual, and social language comprehension in adolescents with autism: an FMRI study.

Language in high-functioning autism is characterized by pragmatic and semantic deficits, and people with autism have a reduced tendency to integrate information. Because the left and right inferior frontal (LIF and RIF) regions are implicated with integration of speaker information, world knowledge, and semantic knowledge, we hypothesized that abnormal functioning of the LIF and RIF regions might contribute to pragmatic and semantic language deficits in autism. Brain activation of sixteen 12- to 18-year-old, high-functioning autistic participants was measured with functional magnetic resonance imaging during sentence comprehension and compared with that of twenty-six matched controls. The content of the pragmatic sentence was congruent or incongruent with respect to the speaker characteristics (male/female, child/adult, and upper class/lower class). The semantic- and world-knowledge sentences were congruent or incongruent with respect to semantic expectancies and factual expectancies about the world, respectively. In the semantic-knowledge and world-knowledge condition, activation of the LIF region did not differ between groups. In sentences that required integration of speaker information, the autism group showed abnormally reduced activation of the LIF region. The results suggest that people with autism may recruit the LIF region in a different manner in tasks that demand integration of social information.

Neural correlates of pragmatic language comprehension in autism spectrum disorders.

Difficulties with pragmatic aspects of communication are universal across individuals with autism spectrum disorders (ASDs). Here we focused on an aspect of pragmatic language comprehension that is relevant to social interaction in daily life: the integration of speaker characteristics inferred from the voice with the content of a message. Using functional magnetic resonance imaging (fMRI), we examined the neural correlates of the integration of voice-based inferences about the speaker's age, gender or social background, and sentence content in adults with ASD and matched control participants. Relative to the control group, the ASD group showed increased activation in right inferior frontal gyrus (RIFG; Brodmann area 47) for speaker-incongruent sentences compared to speaker-congruent sentences. Given that both groups performed behaviourally at a similar level on a debriefing interview outside the scanner, the increased activation in RIFG for the ASD group was interpreted as being compensatory in nature. It presumably reflects spill-over processing from the language dominant left hemisphere due to higher task demands faced by the participants with ASD when integrating speaker characteristics and the content of a spoken sentence. Furthermore, only the control group showed decreased activation for speaker-incongruent relative to speaker-congruent sentences in right ventral medial prefrontal cortex (vMPFC; Brodmann area 10), including right anterior cingulate cortex (ACC; Brodmann area 24/32). Since vMPFC is involved in self-referential processing related to judgments and inferences about self and others, the absence of such a modulation in vMPFC activation in the ASD group possibly points to atypical default self-referential mental activity in ASD. Our results show that in ASD compensatory mechanisms are necessary in implicit, low-level inferential processes in spoken language understanding. This indicates that pragmatic language problems in ASD are not restricted to high-level inferential processes, but encompass the most basic aspects of pragmatic language processing.

Progesterone selectively increases amygdala reactivity in women.

The acute neural effects of progesterone are mediated by its neuroactive metabolites allopregnanolone and pregnanolone. These neurosteroids potentiate the inhibitory actions of gamma-aminobutyric acid (GABA). Progesterone is known to produce anxiolytic effects in animals, but recent animal studies suggest that pregnanolone increases anxiety after a period of low allopregnanolone concentration. This effect is potentially mediated by the amygdala and related to the negative mood symptoms in humans that are observed during increased allopregnanolone levels. Therefore, we investigated with functional magnetic resonance imaging (MRI) whether a single progesterone administration to healthy young women in their follicular phase modulates the amygdala response to salient, biologically relevant stimuli. The progesterone administration increased the plasma concentrations of progesterone and allopregnanolone to levels that are reached during the luteal phase and early pregnancy. The imaging results show that progesterone selectively increased amygdala reactivity. Furthermore, functional connectivity analyses indicate that progesterone modulated functional coupling of the amygdala with distant brain regions. These results reveal a neural mechanism by which progesterone may mediate adverse effects on anxiety and mood.

Declarative memory consolidation in humans: a prospective functional magnetic resonance imaging study.

Retrieval of recently acquired declarative memories depends on the hippocampus, but with time, retrieval is increasingly sustainable by neocortical representations alone. This process has been conceptualized as system-level consolidation. Using functional magnetic resonance imaging, we assessed over the course of three months how consolidation affects the neural correlates of memory retrieval. The duration of slow-wave sleep during a nap/rest period after the initial study session and before the first scan session on day 1 correlated positively with recognition memory performance for items studied before the nap and negatively with hippocampal activity associated with correct confident recognition. Over the course of the entire study, hippocampal activity for correct confident recognition continued to decrease, whereas activity in a ventral medial prefrontal region increased. These findings, together with data obtained in rodents, may prompt a revision of classical consolidation theory, incorporating a transfer of putative linking nodes from hippocampal to prelimbic prefrontal areas.

A Bayesian attractor network with incremental learning.

A realtime online learning system with capacity limits needs to gradually forget old information in order to avoid catastrophic forgetting. This can be achieved by allowing new information to overwrite old, as in a so-called palimpsest memory. This paper describes an incremental learning rule based on the Bayesian confidence propagation neural network that has palimpsest properties when employed in an attractor neural network. The network does not suffer from catastrophic forgetting, has a capacity dependent on the learning time constant and exhibits faster convergence for newer patterns.

Formal schooling influences two- but not three-dimensional naming skills.

The modulatory influence of literacy on the cognitive system of the human brain has been indicated in behavioral, neuroanatomic, and functional neuroimaging studies. In this study we explored the functional consequences of formal education and the acquisition of an alphabetic written language on two- and three-dimensional visual naming. The results show that illiterate subjects perform significantly worse on immediate naming of two-dimensional representations of common everyday objects compared to literate subjects, both in terms of accuracy and reaction times. In contrast, there was no significant difference when the subjects named the corresponding real objects. The results suggest that formal education and learning to read and to write modulate the cognitive process involved in processing two- but not three-dimensional representations of common everyday objects. Both the results of the reaction time and the error pattern analyses can be interpreted as indicating that the major influence of literacy affects the visual system or the interaction between the visual and the language systems. We suggest that the visual system in a wide sense and/or the interface between the visual and the language system are differently formatted in literate and illiterate subjects. In other words, we hypothesize that the pattern of interactions in the functional-anatomical networks subserving visual naming, that is, the interactions within and between the visual and language processing networks, differ in literate and illiterate subjects.

Learning related modulation of functional retrieval networks in man.

The medial temporal lobe has been implicated in studies of episodic memory tasks involving spatio-temporal context and object-location conjunctions. We have previously demonstrated that an increased level of practice in a free-recall task parallels a decrease in the functional activity of several brain regions, including the medial temporal lobe, the prefrontal, the anterior cingulate, the anterior insular, and the posterior parietal cortices, that in concert demonstrate a move from elaborate controlled processing towards a higher degree of automaticity. Here we report data from two experiments that extend these initial observations. We used a similar experimental approach but probed for effects of retrieval paradigms and stimulus material. In the first experiment we investigated practice related changes during recognition of object-location conjunctions and in the second during free-recall of pseudo-words. Learning in a neural network is a dynamic consequence of information processing and network plasticity. The present and previous PET results indicate that practice can induce a learning related functional restructuring of information processing. Different adaptive processes likely subserve the functional re-organisation observed. These may in part be related to different demands for attentional and working memory processing. It appears that the role(s) of the prefrontal cortex and the medial temporal lobe in memory retrieval are complex, perhaps reflecting several different interacting processes or cognitive components. We suggest that an integrative interactive perspective on the role of the prefrontal and medial temporal lobe is necessary for an understanding of the processing significance of these regions in learning and memory. It appears necessary to develop elaborated and explicit computational models for prefrontal and medial temporal functions in order to derive detailed empirical predictions, and in combination with an efficient use and development of functional neuroimaging approaches, to further the understanding of the processing significance of these regions in memory.

Cognitive processing in literate and illiterate subjects: a review of some recent behavioral and functional neuroimaging data.

The study of illiterate subjects, which for specific socio-cultural reasons did not have the opportunity to acquire basic reading and writing skills, represents one approach to study the interaction between neurobiological and cultural factors in cognitive development and the functional organization of the human brain. In addition the naturally occurring illiteracy may serve as a model for studying the influence of alphabetic orthography on auditory-verbal language. In this paper we have reviewed some recent behavioral and functional neuroimaging data indicating that learning an alphabetic written language modulates the auditory-verbal language system in a non-trivial way and provided support for the hypothesis that the functional architecture of the brain is modulated by literacy. We have also indicated that the effects of literacy and formal schooling is not limited to language related skills but appears to affect also other cognitive domains. In particular, we indicate that formal schooling influences 2D but not 3D visual naming skills. We have also pointed to the importance of using ecologically relevant tasks when comparing literate and illiterate subjects. We also demonstrate the applicability of a network approach in elucidating differences in the functional organization of the brain between groups. The strength of such an approach is the ability to study patterns of interactions between functionally specialized brain regions and the possibility to compare such patterns of brain interactions between groups or functional states. This complements the more commonly used activation approach to functional neuroimaging data, which characterize functionally specialized regions, and provides important data characterizing the functional interactions between these regions.

Reactivation of motor brain areas during explicit memory for actions.

Recent functional brain imaging studies have shown that sensory-specific brain regions that are activated during perception/encoding of sensory-specific information are reactivated during memory retrieval of the same information. Here we used PET to examine whether verbal retrieval of action phrases is associated with reactivation of motor brain regions if the actions were overtly or covertly performed during encoding. Compared to a verbal condition, encoding by means of overt as well as covert activity was associated with differential activity in regions in contralateral somatosensory and motor cortex. Several of these regions were reactivated during retrieval. Common to both the overt and covert conditions was reactivation of regions in left ventral motor cortex and left inferior parietal cortex. A direct comparison of the overt and covert activity conditions showed that activation and reactivation of left dorsal parietal cortex and right cerebellum was specific to the overt condition. These results support the reactivation hypothesis by showing that verbal-explicit memory of actions involves areas that are engaged during overt and covert motor activity.

Functional MRI with reduced susceptibility artifact: high-resolution mapping of episodic memory encoding.

Visual episodic memory encoding was investigated using echoplanar magnetic resonance imaging at 2.0 x 2.0 mm2 resolution and 1.0 mm section thickness, which allows for functional mapping of hippocampal, parahippocampal, and ventral occipital regions with reduced magnetic susceptibility artifact. The memory task was based on 54 image pairs each consisting of a complex visual scene and the face of one of six different photographers. A second group of subjects viewed the same set of images without memory instruction as well as a reversing checkerboard. Apart from visual activation in occipital cortical areas, episodic memory encoding revealed consistent activation in the parahippocampal gyrus but not in the hippocampus proper. This finding was most prominently evidenced in sagittal maps covering the right hippocampal formation. Mean activated volumes were 432 +/- 293 microl and 259 +/- 179 microl for intentional memory encoding and non-instructed viewing, respectively. In contrast, the checkerboard paradigm elicited pure visual activation without parahippocampal involvement.

A 4D approach to the analysis of functional brain images: application to FMRI data.

This paper presents a new approach to functional magnetic resonance imaging (FMRI) data analysis. The main difference lies in the view of what comprises an observation. Here we treat the data from one scanning session (comprising t volumes, say) as one observation. This is contrary to the conventional way of looking at the data where each session is treated as t different observations. Thus instead of viewing the v voxels comprising the 3D volume of the brain as the variables, we suggest the usage of the vt hypervoxels comprising the 4D volume of the brain-over-session as the variables. A linear model is fitted to the 4D volumes originating from different sessions. Parameter estimation and hypothesis testing in this model can be performed with standard techniques. The hypothesis testing generates 4D statistical images (SIs) to which any relevant test statistic can be applied. In this paper we describe two test statistics, one voxel based and one cluster based, that can be used to test a range of hypotheses. There are several benefits in treating the data from each session as one observation, two of which are: (i) the temporal characteristics of the signal can be investigated without an explicit model for the blood oxygenation level dependent (BOLD) contrast response function, and (ii) the observations (sessions) can be assumed to be independent and hence inference on the 4D SI can be made by nonparametric or Monte Carlo methods. The suggested 4D approach is applied to FMRI data and is shown to accurately detect the expected signal.

Language processing modulated by literacy: a network analysis of verbal repetition in literate and illiterate subjects.

Previous behavioral and functional neuroimaging data indicate that certain aspects of phonological processing may not be acquired spontaneously, but are modulated by learning an alphabetic written language, that is, learning to read and write. It appears that learning an alphabetic written language modifies the auditory-verbal (spoken) language processing competence in a nontrivial way. We have previously suggested, based on behavioral and functional neuroimaging data, that auditory-verbal and written language interact not only during certain language tasks, but that learning and developing alphabetic written language capacities significantly modulates the spoken language system. Specifically, the acquisition of alphabetic orthographic knowledge has a modulatory influence on sublexical phonological processing and the awareness of sublexical phonological structure. We have suggested that developing an orthographic representation system for an alphabetic written language, and integrating a phoneme-grapheme correspondence with an existing infrastructure for auditory-verbal language processing, will result in a modified language network. Specifically, we suggest that the parallel interactive processing characteristics of the underlying language-processing brain network differ in literate and illiterate subjects. Therefore, the pattern of interactions between the regions of a suitably defined large-scale functional-anatomical network for language processing will differ between literate and illiterate subjects during certain language tasks. In order to investigate this hypothesis further, we analyzed the observed covariance structure in a PET data set from a simple auditory-verbal repetition paradigm in literate and illiterate subjects, with a network approach based on structural equation modeling (SEM). Based on a simple network model for language processing, the results of the present network analysis indicate that the network interactions during word and pseudoword repetition in the illiterate group differ, while there were no significant differences in the literate group. The differences between the two tasks in the illiterate group may reflect differences in attentional modulation of the language network, executive aspects of verbal working memory and the articulatory organization of verbal output. There were no significant differences between the literate and illiterate group during word repetition. In contrast, the network interactions differed between the literate and illiterate group during pseudoword repetition. In addition to differences similar to those observed in the illiterate group between word and pseudoword repetition, there were differences related to the interactions of the phonological loop between the groups. In particular, these differences related to the interaction between Broca's area and the inferior parietal cortex as well as the posterior-midinsula bridge between Wernicke's and Broca's area. In conclusion, the results of this network analysis are consistent with our previously presented results and support the hypothesis that learning to read and write during childhood influences the functional architecture of the adult human brain. In particular, the basic auditory-verbal language network in the human brain is modified as a consequence of acquiring orthographic language skills.

Tickling expectations: neural processing in anticipation of a sensory stimulus.

Predictions of the near future can optimize the accuracy and speed of sensory processing as well as of behavioral responses. Previous experience and contextual cues are essential elements in the generation of a subjective prediction. Using a blocked fMRI paradigm, we investigated the pattern of neural activation in anticipation of a sensory stimulus and during the processing of the somatosensory stimulus itself. Tickling was chosen as the somatosensory stimulus rather than simple touch in order to increase the probability to get a high degree of anticipation. The location and nature of the stimulus were well defined to the subject. The state of anticipation was initiated by attributing an uncertainty regarding the time of stimulus onset. The network of activation and deactivation during anticipation of the expected stimulus was similar to that engaged during the actual sensory stimulation. The areas that were activated during both states included the contralateral primary sensory cortex, bilateral areas in the inferior parietal lobules, the putative area SII, the right anterior cingulate cortex and areas in the right prefrontal cortex. Similarly, common decreases were observed in areas of sensorimotor cortex located outside the area representing the target of stimulus, i.e., areas that process information which is irrelevant to the attended process. The overlapping pattern of change, during the somatosensory stimulation and the anticipation, furthers the idea that predictions are subserved by a neuronal network similar to that which subserves the processing of actual sensory input. Moreover, this study indicates that activation of primary somatosensory cortex can be obtained without intra-modal sensory input. These findings suggest that anticipation may invoke a tonic top-down regulation of neural activity.

Pain-related cerebral activation is altered by a distracting cognitive task.

It has previously been suggested that the activity in sensory regions of the brain can be modulated by attentional mechanisms during parallel cognitive processing. To investigate whether such attention-related modulations are present in the processing of pain, the regional cerebral blood flow was measured using [(15)O]butanol and positron emission tomography in conditions involving both pain and parallel cognitive demands. The painful stimulus consisted of the standard cold pressor test and the cognitive task was a computerised perceptual maze test. The activations during the maze test reproduced findings in previous studies of the same cognitive task. The cold pressor test evoked significant activity in the contralateral S1, and bilaterally in the somatosensory association areas (including S2), the ACC and the mid-insula. The activity in the somatosensory association areas and periaqueductal gray/midbrain were significantly modified, i.e. relatively decreased, when the subjects also were performing the maze task. The altered activity was accompanied with significantly lower ratings of pain during the cognitive task. In contrast, lateral orbitofrontal regions showed a relative increase of activity during pain combined with the maze task as compared to only pain, which suggests the possibility of the involvement of frontal cortex in modulation of regions processing pain.

Statistical limitations in functional neuroimaging. I. Non-inferential methods and statistical models.

Functional neuroimaging (FNI) provides experimental access to the intact living brain making it possible to study higher cognitive functions in humans. In this review and in a companion paper in this issue, we discuss some common methods used to analyse FNI data. The emphasis in both papers is on assumptions and limitations of the methods reviewed. There are several methods available to analyse FNI data indicating that none is optimal for all purposes. In order to make optimal use of the methods available it is important to know the limits of applicability. For the interpretation of FNI results it is also important to take into account the assumptions, approximations and inherent limitations of the methods used. This paper gives a brief overview over some non-inferential descriptive methods and common statistical models used in FNI. Issues relating to the complex problem of model selection are discussed. In general, proper model selection is a necessary prerequisite for the validity of the subsequent statistical inference. The non-inferential section describes methods that, combined with inspection of parameter estimates and other simple measures, can aid in the process of model selection and verification of assumptions. The section on statistical models covers approaches to global normalization and some aspects of univariate, multivariate, and Bayesian models. Finally, approaches to functional connectivity and effective connectivity are discussed. In the companion paper we review issues related to signal detection and statistical inference.

Statistical limitations in functional neuroimaging. II. Signal detection and statistical inference.

The field of functional neuroimaging (FNI) methodology has developed into a mature but evolving area of knowledge and its applications have been extensive. A general problem in the analysis of FNI data is finding a signal embedded in noise. This is sometimes called signal detection. Signal detection theory focuses in general on issues relating to the optimization of conditions for separating the signal from noise. When methods from probability theory and mathematical statistics are directly applied in this procedure it is also called statistical inference. In this paper we briefly discuss some aspects of signal detection theory relevant to FNI and, in addition, some common approaches to statistical inference used in FNI. Low-pass filtering in relation to functional-anatomical variability and some effects of filtering on signal detection of interest to FNI are discussed. Also, some general aspects of hypothesis testing and statistical inference are discussed. This includes the need for characterizing the signal in data when the null hypothesis is rejected, the problem of multiple comparisons that is central to FNI data analysis, omnibus tests and some issues related to statistical power in the context of FNI. In turn, random field, scale space, non-parametric and Monte Carlo approaches are reviewed, representing the most common approaches to statistical inference used in FNI. Complementary to these issues an overview and discussion of non-inferential descriptive methods, common statistical models and the problem of model selection is given in a companion paper. In general, model selection is an important prelude to subsequent statistical inference. The emphasis in both papers is on the assumptions and inherent limitations of the methods presented. Most of the methods described here generally serve their purposes well when the inherent assumptions and limitations are taken into account. Significant differences in results between different methods are most apparent in extreme parameter ranges, for example at low effective degrees of freedom or at small spatial autocorrelation. In such situations or in situations when assumptions and approximations are seriously violated it is of central importance to choose the most suitable method in order to obtain valid results.

Learning-related effects and functional neuroimaging.

A fundamental problem in the study of learning is that learning-related changes may be confounded by nonspecific time effects. There are several strategies for handling this problem. This problem may be of greater significance in functional magnetic resonance imaging (fMRI) compared to positron emission tomography (PET). Using the general linear model, we describe, compare, and discuss two approaches for separating learning-related from nonspecific time effects. The first approach makes assumptions on the general behavior of nonspecific effects and explicitly models these effects, i.e., nonspecific time effects are incorporated as a linear or nonlinear confounding covariate in the statistical model. The second strategy makes no a priori assumption concerning the form of nonspecific time effects, but implicitly controls for nonspecific effects using an interaction approach, i.e., learning effects are assessed with an interaction contrast. The two approaches depend on specific assumptions and have specific limitations. With certain experimental designs, both approaches may be used and the results compared, lending particular support to effects that are independent of the method used. A third and perhaps better approach that sometimes may be practically unfeasible is to use a completely temporally balanced experimental design. The choice of approach may be of particular importance when learning-related effects are studied with fMRI.

Effective auditory-verbal encoding activates the left prefrontal and the medial temporal lobes: A generalization to illiterate subjects.

Recent event-related FMRI studies indicate that the prefrontal (PFC) and the medial temporal lobe (MTL) regions are more active during effective encoding than during ineffective encoding. The within-subject design and the use of well-educated young college students in these studies makes it important to replicate these results in other study populations. In this PET study, we used an auditory word-pair association cued-recall paradigm and investigated a group of healthy upper middle-aged/older illiterate women. We observed a positive correlation between cued-recall success and the regional cerebral blood flow of the left inferior PFC (BA 47) and the MTLs. Specifically, we used the cued-recall success as a covariate in a general linear model and the results confirmed that the left inferior PFC and the MTL are more active during effective encoding than during ineffective encoding. These effects were observed during encoding of both semantically and phonologically related word pairs, indicating that these effects are robust in the studied population, that is, reproducible within group. These results generalize the results of Brewer et al. (1998, Science 281, 1185-1187) and Wagner et al. (1998, Science 281, 1188-1191) to an upper middle aged/older illiterate population. In addition, the present study indicates that effective relational encoding correlates positively with the activity of the anterior medial temporal lobe regions.

Dynamic changes in the functional anatomy of the human brain during recall of abstract designs related to practice.

In the present PET study we explore some functional aspects of the interaction between attentional/control processes and learning/memory processes. The network of brain regions supporting recall of abstract designs were studied in a less practiced and in a well practiced state. The results indicate that automaticity, i.e., a decreased dependence on attentional and working memory resources, develops as a consequence of practice. This corresponds to the practice related decreases of activity in the prefrontal, anterior cingulate, and posterior parietal regions. In addition, the activity of the medial temporal regions decreased as a function of practice. This indicates an inverse relation between the strength of encoding and the activation of the MTL during retrieval. Furthermore, the pattern of practice related increases in the auditory, posterior insular-opercular extending into perisylvian supramarginal region, and the right mid occipito-temporal region, may reflect a lower degree of inhibitory attentional modulation of task irrelevant processing and more fully developed representations of the abstract designs, respectively. We also suggest that free recall is dependent on bilateral prefrontal processing, in particular non-automatic free recall. The present results confirm previous functional neuroimaging studies of memory retrieval indicating that recall is subserved by a network of interacting brain regions. Furthermore, the results indicate that some components of the neural network subserving free recall may have a dynamic role and that there is a functional restructuring of the information processing networks during the learning process.